2.1. NEURONAL CELL DEATH AND THE ROLE OF NEUROTROPHIC FACTORS IN THE DEVELOPMENT OF THE NERVOUS SYSTEM
Throughout many parts of the vertebrate nervous system many more neurons are present during early development than are found in the adult animal. Periods of early development are characterized by waves of naturally occurring neuronal cell death (Carr and Simpson, 1978, J. Comp. Neurol., 182:727-740; Cowan et al., 1984, Science 225:1258-1265). The survival, differentiation and maturation of developing neurons may be regulated by environmental or `epigenetic` factors rather than by a strict intrinsic genetic program. For example, experimental manipulations of the chick embryo have shown that transplantation or extirpation of peripheral "target fields", such as a limb bud or the eye, at early stages in chick development can result in a corresponding increase or decrease, respectively, in the number of sensory, sympathetic, parasympathetic or motorneurons adjacent to the enlarged or depleted target field (Hamburger, 1934, J. Exp. Zool. 68:449; Hollyday and Hamburger, 1976, J. Comp. Neurol., 170:311-321; Landmesser and Pilar, 1976, J. Cell. Biol., 68:357-374). A target field may only support a limited number of neurons, and a normal part of the developmental process may be the pruning of an excess number of neurons to match the "neurotrophic" capacity of the target tissue. The discovery and isolation of the protein now called nerve growth factor (NGF) has led to a molecular hypothesis of how a target may be able to regulate the number of neurons which survive and innervate that tissue (Levi-Montalcini et al., 1968, Physiol Rev., 48:524-569; Thoenen and Barde, 1980, Physiol Rev., 60:1284-1335).
It is now well established, at least in the peripheral nervous system, that neuronal target tissues synthesize and release limited quantities of various neurotrophic molecules which are critical to the survival of specific types of neurons (Korsching and Thoenen, 1983, Proc. Natl. Acad. Sci. U.S.A. 80:3513-3516; Heumann et al., 1984, EMBO J. 3:3183-3189; Shelton and Reichardt, 1984, Proc. Natl. Acad. Sci U.S.A. 81:7051-7955; Korsching and Thoenen, 1985, Neurosci. Lett. 54:201-205).